An Evidence-Based Guideline for the Pre-Operative Sedation of Children

Journal of Pediatrics and Neonatal Care

Abstract Review Article

There are numerous sedative pharmacological agents currently administered to Volume 2 Issue 6 - 2015 children as premedicants to facilitate the induction of anaesthesia. When pre- operative sedation is required, selection of the appropriate drug is imperative to Deborah M Fradkin*, Victoria L Scott- provide adequate anxiolysis whilst minimising unwanted side effects. We review Warren, Rita Vashisht and Sian E Rolfe the literature regarding the merits and limitations of the commonly used agents and suggest evidence based practical guidance. For the anxious but cooperative Department of Paediatric Anaesthesia, Royal Manchester Children’s Hospital, England child, oral midazolam is often adequate; however with more anxious younger and uncooperative children, combined oral midazolam and ketamine is more *Corresponding author: DM. Fradkin, Department of effective. Other oral benzodiazepines and oral clonidine all have their role when Paediatric Anaesthesia, Royal Manchester Children’s used in the appropriate circumstances. Intranasal clonidine is useful in the child Hospital, Oxford Road, Manchester, M13 9WL, England, Tel: refusing oral medication. Intramuscular ketamine should be reserved for extreme 0161 701 1264; Email: circumstances, administered only by anaesthetists experienced in its use, with full monitoring and resuscitative equipment immediately available. Received: August 15, 2015 | Published: September 08, 2015 Keywords: Conscious sedation; Anxiolytics; Paediatric Anaesthetics; Premedication; Preoperative care

Abbreviations: PO: Oral; IN: Intranasal; IM: Intramuscular; always obvious. Use of an inappropriate agent or dose can produce side effects such as cardiorespiratory depression. Conversely, an inappropriate agent may lead to inadequate sedation of an already IntroductionOTMF: Oral Transmucosal Fentanyl; GABA: ƴ-Aminobutyric acid anxious non-cooperative child, causing increased distress for both the child and parent, resulting in abandoning the induction Information regarding the variety of pre-medications and and delaying surgery. their appropriateness in different clinical situations is dispersed widely within the literature and therefore not easily comparable This document reviews the available literature and provides at a glance. Working at a tertiary paediatric hospital, with a large guidance on the prescribing and administration of pre-operative turnover of trainees with limited prior exposure to paediatric sedative drugs to facilitate the induction of anaesthesia in healthy anaesthesia, we felt it was imperative to create robust evidence children. Its use is not intended for procedural sedation or based guidelines, bringing together the information available into sedation to facilitate diagnostic investigations. The premedication one easily accessible, clear, concise and comprehensive document. of children with severe cardiorespiratory or neurological This guidance, although produced for a tertiary hospital, is a disease is beyond the scope of this document and will require a useful tool to facilitate safe practice and minimise inappropriate personalised approach determined by a consultant anaesthetist. drug selection and dosing for any anaesthetist with an interest in Similarly, in individual cases, drugs and dosages not covered in paediatrics. this guideline may be considered appropriate by a consultant anaesthetist. Premedication is drug treatment given to a patient usually before medical or surgical procedures. The aim of premedication These medications should be prescribed only by anaesthetists in children and young people is to produce a relaxed state with and following thorough anaesthetic assessment of the patient. Of reduced anxiety and increased compliance, allowing the patient note, as rectal administration of sedation is not favoured by either to tolerate and co-operate with the necessary procedure. the anaesthetist or parents at our trust this has not been included This is commonly achieved by appropriate administration of in our guidelines. pharmacological agents, typically sedative or analgesic. After effective premedication, patients may exhibit an altered level of The practicalities and logistics of paediatric patients consciousness but should retain the ability to independently and having preoperative sedation must always be considered continuously maintain a patent airway, follow verbal commands, prior to prescribing and administration. A suggested practical and respond appropriately to tactile stimulation [1-3]. management to optimise patient care and minimise risk is suggested in our supporting information (section 9). The spectrum of children requiring sedative premedication for induction of anaesthesia varies from the anxious but Discussion cooperative, the anxious and uncooperative, to those with severe Guideline for oral premedication would not tolerate induction of anaesthesia without sedation. Midazolam: Oral (PO) premedication is easier to administer and Withdevelopmental a large selection delay and of behaviouralavailable pharmacological difficulties some agents, of whom the better accepted than other possible routes of drug administration most appropriate premedicant for an individual child is not [4]. The ability to hide PO premedication within a carrier liquid (a

useful for the uncooperative patient with behavioural or secretion or postoperative nausea and vomiting [4,18,19] and flavoured drink or ibuprofen syrup if appropriate) is particularly withadequate no evidence sedation of emergence without delirium. significantly At higher increasing doses than oral administration of a small volume of liquid (less than 10mls) pre- recommended (>5mg/kg) it can lead to an increase in nystagmus operativelylearning difficulties. does not Oflead note to anthere increased is evidence aspiration that the risk paediatric [5]. [4], vomiting and hallucinations [23]. Combined midazolam and ketamine can lead to effective benzodiazepine, it acts as both an anxiolytic and hypnotic agent, anxiolysis without sedation. Funk found that excess sedation did modulatingPO midazolam the effects is aof commonlythe main inhibitory used first neurotransmitter line agent. A not occur [18], and Warner stated all children in their study who were sleeping were easy to rouse, and the majority were awake at GABAA receptors [6]. The dose of 0.5mg/kg has been well and calm (in this study 0.02mg/kg atropine, itself mildly sedative, establishedwithin the central through nervous various system, studies, ƴ-Aminobutyric with lower doses acid providing (GABA), was also used) [14]. When sedation does occur, it is normally inadequate anxiolysis [5,7] and higher doses potentially causing within 15-30minutes of administration [4]. In addition, there dysphoric reactions [8], ataxia and prolonged sedation, without is no evidence of hypoxia, with studies demonstrating oxygen improving anxiolysis [9]. Respiratory and cardiovascular saturations remaining above 97% [18] and 99% [19] with no depression may occur [6,10]. Administration of 0.5mg/kg oral change in respiratory rate [19]. midazolam (maximum dose 20mg) will provide anxiolysis as early as 15 minutes, with anterograde amnesia occurring as early as premedication with a combination of ketamine and midazolam 10 minutes post dose; however peak sedation may take up to 30 Although some studies find no delay in recovery [18], minutes to occur [11,12]. The evidence that PO midazolam leads in discharge from recovery postoperatively [17,19], with a mean to delayed discharge from recovery is variable [13]. However, the recoverymay lead dischargeto a slight time (although of 51 minutesnot statistically in one study significant) [19], and delay 54 minutes in another [17] (compared to the control of 40 minutes, disadvantage of a potentially prolonged recovery stay. benefit associated with appropriate premedication outweighs the and 39 minutes with midazolam alone, respectively). Combined midazolam and ketamine: Midazolam as a sole A combination of midazolam and ketamine should therefore to administer, with a rapid onset and relatively short duration. in anxious and uncooperative children and children with Howeveragent fits itsmany degree of the of criteria success of makes an ideal it premedicant,less than ideal. being Good easy or behaviouralbe considered or developmental as first-line choice issues. for However, paediatric when premedication this option excellent results are only seen in 60-80% of patients with many is contraindicated (e.g. a history of paradoxical excitation with studies reporting lower success rates [5,8,14]. Children who are midazolam) we do not recommend ketamine alone. This is more anxious and emotional, or those below four years old, are more likely to be inadequately sedated by midazolam alone [15]. dose to produce adequate sedation and anxiolysis [4] leading Children with diagnosed developmental delay and/or behavioural tobecause increased its use side as effects. a sole In agent this requiressituation, a alternatives significantly such greater as clonidine, lorazepam or temazepam may be useful premedicants. effective anxiolysis [2,16]. However such doses expose them todifficulties risks of oftensedation need such larger as dosesreduced of sedativerespiratory agents drive, to providealtered Clonidine: sedative, anxiolytic, analgesic and antiemetic properties. Agonism Clonidine is a partial α2 adrenoceptor agonist with patencyA number of the ofairway, studies and have reduction reviewed of protective and assessed reflexes. the use of a combination of sedative agents for effective premedication causingof α2 receptors anxiolysis in the and locus sedation. ceruleus of the pons leads to decreased [14,17-19]. Midazolam with ketamine is an effective combination noradrenergic outflow, increasing firing of inhibitory neurons, in complex cases such as children with developmental delay Although used as an antihypertensive, it produces minimal haemodynamic changes in healthy children. It does, however is key [2,3,20]. This allows a reduced dose of the individual obtund the stress response to intubation when given as and/or behavioural difficulties where behaviour modification a premedicant [24]. Clonidine does not cause respiratory compromise [3,20]. Each drug reduces some of the adverse effects depression, has no effect on cognitive function/memory [24] and ofdrugs, the other providing whilst a saferenhancing profile the against anxiolytic airway and andsedative respiratory effect. may decrease perioperative requirements of volatile anaesthetics Importantly, the success rate of the combination is superior to and opioids [25]. Clonidine has been used to reduce the risk of either drug given alone [21]. and treat emergence/post-op delirium in children [26,27,29]. Ketamine is a phencyclidine derivative acting on the central The sedation produced by clonidine is very similar to nervous system as an antagonist at N-Methyl-D-aspartate normal tiredness/sleep in contrast to the sedation caused by (NMDA) receptors [6,10], inhibiting cerebral excitatory pathways midazolam which more closely resembles alcohol intoxication [6]. Ketamine also interacts with opioid receptors and has some local anaesthetic action [22]. It can be used to induce general comparative pre-operative sedation to midazolam [25,29,30,31], anaesthesia and to provide effective analgesia in both acute and whilst[24]. A others number report of studies more effectivefind that sedation, clonidine better 4mcg/kg acceptance produces of chronic pain [6]. Cardiovascular stimulation can occur with mild oral clonidine, and a higher degree of parental satisfaction with respiratory depression but with preservation of laryngeal and clonidine compared to midazolam [25,32,33]. Clonidine also has analgesic effects mediated via the activation of postsynaptic Three mg/kg ketamine should be added to 0.5mg/kg pharyngeal reflexes. cord, inhibiting Substance P release. Several studies show that midazolam and given orally. This dose of ketamine provides α2 adrenoceptors in the substantia gelatinosa of the spinal

Citation: Fradkin DM, Scott-Warren VL, Vashisht R, Rolfe SE (2015) An Evidence-Based Guideline for the Pre-Operative Sedation of Children. J Pediatr Neonatal Care 2(6): 00095. DOI: 10.15406/jpnc.2015.02.00095 Copyright: An Evidence-Based Guideline for the Pre-Operative Sedation of Children ©2015 Fradkin et al. 3/7

clonidine premedication is associated with lower levels of [35]. It should be noted however that doses of 0.05mg/kg may postoperative pain than midazolam [26,29,33,34]. This might lead to postoperative restlessness and vomiting [40]. make clonidine a particularly appropriate choice for sedation of Temazepam has been used as a paediatric premedicant in the child undergoing a painful procedure. doses of 0.3-0.5mg/kg administered 1-2 hours preoperatively The dose of 4mcg/kg of oral clonidine and 2-4mcg/kg of [41,42]. Higher doses (0.5mg/kg- 1mg/kg) have been used when intranasal (IN) clonidine have been suggested in guidelines from sedating children for MRI scanning and dental procedures without other paediatric surgical centres [35,36], a recent review article adverse events [43,44]. The maximum dose that may be given is [37], and used safely in many studies [25,26,29,38]. However, 20mg. An oral solution of 10mg/5ml is available. Guidelines in one study did report two episodes of bradycardia in patients other institutions suggest a dose of 10-20mg in children 12-18 premedicated with clonidine [33] and some investigators chose years old [35]. to combine the clonidine with 20mcg/kg atropine [39]. This review demonstrates that for an anxious uncooperative Lorazepam and Temazepam: Lorazepam is available as tablet and liquid formation for oral administration. However the liquid midazolam and ketamine is recommended. Clonidine, lorazepam form is not licensed for use in children and is expensive with a andchild, temazepam midazolam are alone alternative is often insufficient, agents that andmay the be combination appropriate inof short shelf life. The tablets can be crushed and dispersed for certain circumstances. Table 1 summarises the doses and timing administration. It can be prescribed for children over 5 years old, of administration of these oral premedicants. The presentation, and should be given one hour prior to induction of anaesthesia, cautions and contraindications of these drugs are expanded upon with a duration of action of up to 12 hours. An oral dose of 0.025- in the supporting information (section 9). 0.05mg/kg (maximum 4mg) decreases pre-operative anxiety. Children above 12 years old can be given a dose of 1-4mg orally

Table 1: Oral premedication

Drug Name and Route of Dose Timing of Administration Notes Administration

Midazolam PO 0.5mg/kg 30 minutes prior to induction Maximum dose 20mg

Midazolam(M) & Ketamine Maximum Midazolam 0.5mg/kg (M) & 3mg/ kg (K) 30 minutes prior to induction (K) PO dose 20mg

Maximum dose Clonidine PO 4mcg/kg 45-60 minutes prior to induction 300mcg.

0.025-0.05mg/kg (maximum Caution with dose of Lorazepam PO 60 minutes prior to induction 4mg) 0.05mg 0.3-0.5 mg/kg 10-20mg in children Temazepam PO (Maximum 20mg) 60 minutes prior to induction 12-18yrs old

Guideline for intranasal premedication situation IN clonidine (which is tasteless) should be considered. Of note, a recent study comparing IN Midazolam with IN Some children may not be amenable to taking oral Clonidine mixed with atropine found clonidine gave a better premedication, especially due to the bitter taste of oral midazolam. [39]. Table 2 shows the dose and timing of administration for IN of recipients [13,45] and is therefore not recommended. In this clonidine.mask acceptance and recovery profile with comparable anxiolysis IN midazolam causes significant discomfort in a high proportion Table 2: Intranasal Premedication

Drug Name and Route of Dose Timing of Administration Notes Administration Maximum dose 300mcg. Consider Clonidine IN 2mcg/kg 45-60 minutes prior to induction addition of 20mcg/kg atropine IN.

Guideline for intramuscular premedication must be prescribed and administered by an experienced paediatric anaesthetist only. Administration should either be in the recovery If administration by no other route is possible, but sedation room, or if on the ward, in a side room with a anaesthetic considered essential to successful induction of anaesthesia, department practitioner, monitoring and resuscitation equipment intramuscular (IM) ketamine is recommended. A dose of 4-5mg/ present throughout. As soon as the patient is drowsy they should kg produces adequate sedation within 5-10 minutes [46], as be transferred to theatre. highlighted in table 3. Sedation can be profound so IM ketamine

Table 3: Intramuscular premedication

Drug Name and Route of Dose Timing of Administration Notes Administration Anaesthetist to be present from Ketamine IM 4-5mg/kg 5-10 minutes prior to induction time of administration to post-operative recovery

Other sedative premedicants not currently recommended for routine use it a full α2 agonist compared with the partial agonist clonidine Oral transmucosal fentanyl (OTMF) lollipops have been which has a comparable specificity ratio of 200:1. Its greater α2 used at a dose of 15-20mcg/kg for the preoperative sedation of specificity and shorter elimination half-life are likely to result in a children. It is as effective at producing anxiolysis and compliance moreDexmedetomidine favourable pharmacological has a US and proﬁle UK forlicence sedation for sedation[54]. of with anaesthetic induction as midazolam with the advantage of intubated patients, being launched in the UK in 2011. In 2008 it being appealing to children. In addition, OTMF has been shown was approved in the US for use in non-intubated patients requiring to have better emergence characteristics than midazolam with no sedation prior to and/or during procedures, but it does not hold post-operative behavioural changes [47]. a licence for use in children. Nonetheless, the evidence for the

OTMF causes high levels (>80%) of facial pruritis [47-49], in children is mounting [54,55]. It also demonstrates anxiolytic, although this does not seem to cause distress to children [47]. antisialogogue,efficacy and safety sympatholytic of Dexmedetomidine and antiemetic as a sedative properties premedicant [54] However, a rate of peri-operative vomiting of 50% has been and does not cause respiratory depression even in high doses repeatedly found in studies [47,50] with one study terminating its [55,57]. We anticipate the inclusion of Dexmedetomidine in future protocol early because 3 out of 10 patients vomited preoperatively sedation guidelines as its evidence base and familiarity grow. (2 immediately prior to induction) [48]. The routine use of OTMF therefore is not currently recommended in this guideline, however Conclusion if chosen by a consultant anaesthetist as the best premedicant for a particular child, a dose of 15-20mcg/kg is recommend. Appropriate pre-operative sedation is an invaluable tool for the paediatric anaesthetist and careful consideration is needed Melatonin has several applications for sleep regulation and to decide the best agent for each child. In those children with sedation in adults, but its use in children as a pre-operative sedative has not yet been fully established [51]. A dose of 0.25-0.5 to successful induction of anaesthesia, a combination of oral mg/kg can be as effective a pre-operative anxiolytic as midazolam behavioural difficulties, where anxiolysis is a pre-requisite reducing the post-anaesthetic excitation that can be seen with Acknowledgementmidazolam and ketamine should be considered as first line. (although some studies refute this [52]), whilst significantly midazolam. In addition it has a lower incidence of post-anaesthetic We acknowledge the contribution of Dr King et al of Nottingham sleep disturbance compared to placebo or midazolam [51]. The Children’s Hospital and Dr Beringer et al of University Hospitals effect of melatonin is lessened in the morning, or immediately Bristol NHS Foundation Trust who kindly allowed us to view and after waking, and increased if the patient is sleep deprived [53]. reference their guidelines in the development of this document. melatonin as a pre-operative sedative, however, if deemed to be Supporting Information theThere premedicant is insufficient of choice evidence by a consultant to support anaesthetist the routine a dose use of 0.25-0.5mg/kg 60 minutes prior to induction would be in keeping Contraindications, cautions, and presentation of with the literature [51,53]. suggested agents Tables (4-6).

Dexmedetomidine is an α2 adrenoceptor agonist with a Tablespecificity 4: Benzodiazepines of 1600:1 for α2 receptors compared to α1. This makes

Contraindications Severe respiratory depression, upper airway compromise, neuromuscular weakness, previous hyper-excitability [35]. Cautions Cardiorespiratory disease, neuromuscular disease, drug and alcohol abuse. Hypovolaemia, hypo- thermia, vasoconstriction [58]. Hepatic or renal impairment, severe personality disorders [35].

Presentation Lorazepam: Tablet may be crushed. Temazepam:Midazolam: PO Oral available solution in 10mg/ml. 2.5mg/ml syrup, blackcurrant flavoured. Note, see BNFc for full details

Table 5: Ketamine

Contraindications Hypertension, stroke, acute porphyria (35). Cautions Severe cardiac disease. Epilepsy/seizures, psychosis, thyroid disorder, glaucoma (35). Dehydra- tion, respiratory infection (58). Presentation IV preparation can be given orally. Available in 10mg/ml & 50mg/ml. Note, see BNFc for full details

Table 6: Clonidine

Contraindications Bradyarrhythmias secondary to second or third degree AV block or sick sinus syndrome Cautions Concomitant administration of Methylphenidate. Mild/moderate bradyarrhythmia, constipation, polyneuropathy, Raynaud’s syndrome or other occlusive peripheral vascular disease, history of depression. Presentation 100 micrograms tablets can be crushed and dispersed in water. Intravenous preparation (150mcg/ ml) is tasteless and can be given orally, diluted with water. Note, see BNFc for full details Practical management of pre-operative sedation References Prior to administration of the sedative premedication. 1. National Institute for Clinical Excellence Clinical Guideline 112 (2010) Sedation in children and young people (Sedation for diagnostic and i. The patient must have an allocated bed. therapeutic procedures in children and young people). ii. It must be >6 hours since the child consumed food and > 2 2. Cote CJ, Wilson S (2006) Guideline for Monitoring and Management of Paediatric Patients During and After Sedation for Diagnostic and Therapeutic Procedures. Paediatrics 118(6): 2587-2602. iii. hoursFollowing since pre-operativeclear fluids. assessment, the premedication should be prescribed only by an anaesthetist. 3. Abdallah C, Hannallah R (2011) Premedication of the child undergoing surgery. Middle East Journal of Anaesthesiology 21(2): 165-176. iv. The premedicant might be prescribed with ‘on-call’ listed as 4. Turhanoglu S, Kararmaz A, Ozyilmaz MA, Kaya S, Tok D (2003) Effects the time of administration. In this situation, the prescribing of different doses of oral ketamine for premedication of children. Eur J anaesthetist will telephone the ward to tell them when to Anaesthesiol 20(1): 56-60. administer the premedicant. 5. Feld LH, Negus JB, White PF (1990) Oral midazolam preanaesthetic v. If the child refuses, vomits or spits out the drug, contact the medication in paediatric outpatients. Anesthesiology 73(5): 831-834. anaesthetist who prescribed the drug. 6. Peck TE, Hill SA, Williams M (2008) Pharmacology for Anaesthesia vi. After receiving the premedicant the child should remain on and Intensive Care. (3rd edn), Cambridge Medicine. USA, pp. 378. the ward under the direct supervision of a responsible adult, 7. Parnis SJ, Foate JA, Van Der Walt JH, Short T, Crowe CE (1992) Oral such as a parent or guardian. midazolam is an effective premedication for children having day-stay anaesthesia. Anaesth Intensive Care 20(1): 9-14. vii. When the child becomes drowsy they should lie in a bed. If the child becomes sedated (V on AVPU scale) continuous oxygen 8. McMillan CO, Spahr-Schopfer IA, Sikich N, Hartley E, Lerman J (1992) saturation should be monitored. If the oxygen saturation Premedication of children with oral midazolam. Can J Anaesth 39(6): reads < 96%, oxygen should be applied via facemask and 545-550. the prescribing anaesthetist/ on-call anaesthetist contacted 9. Cox RG, Nemish U, Ewen A, Crowe MJ (2006) Evidence-based clinical immediately. update: does premedication with oral midazolam lead to improved behavioural outcomes in children? Can J Anaesth 53(12): 1213-1219. viii. In addition to continuous oxygen saturation monitoring and general observation by nursing staff, the child should have 10. Yentis S, Hirsch N, Smith G (2009) Anaesthesia and Intensive Care the following parameters recorded at 15 minute intervals as a A-Z; An Encyclopaedia of Principles and Practice. (4th edn), Churchill minimum: Livingstone, England, pp. 584. 11. Levine M, Spahr-Schopfer I, Hartley E, Lerman J, MacPherson B (1993) • Oxygen saturation Oral midazolam premedication in children: the minimum time interval • Respiratory rate for separation from parents. Can J Anaesth 40(8): 726-729. • Pulse 12. Kain ZN, Hofstadter MB, Mayes LC, Krivutza DM, Alexander G, et al. (2000) Midazolam, effects on amnesia and anxiety in children. • Conscious level (AVPU score: Alert, Verbal, Pain, Anaesthesiology 93(3): 676-684. Unresponsive) 13. McCann ME, Kain ZN (2001) The management of preoperative anxiety ix. The child must be transported to theatre on a bed or trolley. in children: An update. Anesth Analg 93(1): 98-105.

14. Warner DL, Cabaret J, Velling D (1995) Ketamine plus midazolam, a 31. Zub D, Berkenbosch JW, Tobias JD (2005) Preliminary experience with most effective paediatric oral premedicant. Paediatric Anaesthesia oral dexmedetomidine for procedural and anaesthetic premedication. 5(5): 293-295. Pediatr Anesth 15(11): 932-938. 15. Kain ZN, MacLaren J, McClain BC, Saadat H, Wang SM, et al. (2007) 32. Almenrader N, Passariello M, Coccetti B, Haiberger R, Pietropaoli P Effects of age and emotionality on the effectiveness of midazolam (2007) Premedication in children: A comparison of oral midazolam administered preoperatively to children. Anesthesiology 107(4): 545- and oral clonidine. Paediatr Anaesth 17(12): 1143-1149. 552. 33. Cao J, Shi X, Miao X, Xu J (2009) Effects of premedication of midazolam 16. Tan L, Meakin G (2010) Anaesthesia for the Uncooperative Child. or clonidine on perioperative anxiety and pain in children. BioScience Continuing Education in Anaesthesia Critical Care & Pain 10(2): 48- Trends 3(3): 115-118. 52. 34. Galindo Palazuelos M, Díaz Setién NA, Rodríguez Cundín P, Manso 17. Trabold B, Rzepecki A, Sauer K, Hobbhahn J (2002) A comparison Marín FJ, Castro Ugalde A (2008) Premedication with intraoperative of two different doses of ketamine with midazolam and midazolam clonidine and low-dose ketamine in outpatient laparoscopic cholecys- tectomy. Rev Esp Anestesiol Reanim 55(7): 414-417. anaesthesia in children. Paediatric Anaesthesia 12(8): 690-693. alone as oral preanaesthetic medication on recovery after sevoflurane 35. King H, Maguire A, Cory P (2011) Guideline for premedication in chil- 18. Funk W, Jakob W, Riedl T, Taeger K (2000) Oral preanaesthetic dren and young people where midazolam may not be effective. Core medication for children: double-blind randomized study of a Paediatric Anaesthesia Group. Nottingham Children’s Hospital. combination of midazolam and ketamine vs midazolam or ketamine alone. Br J Anaesth 84(3): 335-340. 36. Beringer R, Gage S (2011) Pre-operative sedative medication for children. University Hospitals Bristol NHS FT. 19. Beebe DS, Belani KG, Chang PN, Hesse PS, Schuh JS, et al. (1992) Effectiveness of preoperative sedation with rectal midazolam, 37. O’Sullivan M, Wong GK (2013) Preinduction techniques to relieve ketamine, or their combination in young children. Anesth Analg 75(6): anxiety in children undergoing general anaesthesia. CEACCP 13(6): 880-884. 196-199. 20. Courtman S (2013) The Uncooperative Child (accessed 21st Mar 38. Stella MJ, Bailey AG (2008) Intranasal clonidine as a premedicant: 2013). three cases with unique indications. Paediatr Anaesth 18(1): 71-73. 21. 39. Mitra S, Kazal S, Kanand L (2013) Intranasal Clonidine vs. Midazolam Paediatric Anaesthesia. 18(3): 198-207. as Premedication in Children: A Randomized Controlled Trial. Indian Courtman S, Mumby D (2008) Children with learning difficulties. Paediatrics. 22. Pai A, Heining M (2007) Ketamine. Continuing Education in Anaesthe- sia, Critical Care & Pain 7(2): 59-63. 40. Bissonette B (2002) Paediatric anaesthesia, Principles and Practice. (1st edn), McGraw Hill, USA. 23. Roelofse JA, Louw LR, Roelofse PG (1998) A double blind randomised comparison of oral trimeprazine-methadone and ketamine-midazol- 41. van den Berg AA, Montoya-Pelaez LF, Halliday EM, Hassan I, Baloch am for sedation of paediatric dental patients for oral surgical proce- MS, et al. Analgesia for adenotonsillectomy in children and young dures. Anesth Prog 45(1): 3-11. adults: a comparison of tramadol, pethidine and nalbuphine. Eur J An- aesthesiol 16(3): 186-194. 24. Rosenbaum A, Kain ZN, Larsson P, Lönnqvist PA, Wolf AR (2009) Pro-Con Debate: The place of premedication in paediatric practice. 42. Browne BL, Prys-Roberts C, Wolf AR (1992) Propofol and alfentanil Paediatric Anaesthesia 19: 817-828. in children: infusion technique and dose requirement for total i.v. anaesthesia. Br J Anaesth 69(6): 570-576. 25. Bergendahl H, Lonnqvist P, Eksborg S (2006) Clonidine in paediatric anaesthesia: review of the literature and comparison with benzodi- 43. Woodthorpe C, Trigg A, Alison G, Sury M (2007) Nurse led sedation azepines for premedication. Acta Anaesthesiol Scand 50(2): 135-143. for paediatric MRI: progress and issues. Paediatr Nurs 19(2): 14-18. 26. Bergendahl HT, Lönnqvist PA, Eksborg S, Ruthström E, Nordenberg 44. Sury MR, Hatch DJ, Deeley T, Dicks-Mireaux C, Chong WK (1999) L, et al. (2004) Clonidine vs Midazolam in children undergoing ade- Development of a nurse-led sedation service for paediatric magnetic notonsillectomy: a prospective randomised clinical, controlled trial. resonance imaging. Lancet 353(9165): 1667-1671. Acta Anaesthesiol Scand 48(10): 1292-1300. 45. Ljungman G, Kreuger A, Andreasson S, Gordh T, Sörensen S (2000) 27. Tesoro S, Mezzetti D, Marchesini L, Peduto VA (2005) Clonidine treat- Midazolam nasal spray reduces procedural anxiety in chidren. Paediatrics 105(1 Pt 1): 73-78. Analg 101(6): 1619-1622. 46. Bhatt S, Neupane Bk (2005) Intramuscular ketamine pre-medication ment for agitation in children after sevoﬂurane anaesthesia. Anesth 28. - to separate children from their parents. Nepal Med Coll J 7(2): 131- rane-induced agitation in children. Anesth Analg 93(2): 335-338. 133. Kulka PJ, Bressem M, Tryba M (2001) Clonidine prevents sevoﬂu 29. Schmidt AP, Valinetti EA, Bandeira D, Bertacchi MF, Simões CM, et 47. Howell, TK, Smith S, Rushman C, Walker RW, Radivan F (2002) A al. Effects of preanaesthetic administration of midazolam, clonidine, comparison of oral transmucosal fentanyl and oral midazolam for or dexmedetomidine on postoperative pain and anxiety. Paediatr premedication in children. Anaesthesia 57(8): 778-817. Anaesth 17(7): 667-674. 48. Epstein RH, Mendel HG, Witkowski TA, Waters R, Guarniari KM (1996) 30. Bergendahl H, Lönnqvist PA, Eksborg S (2005) Clonidine: an - alternative to benzodiazepines for premedication in children. Curr operative Sedation in Young Children. Anesth Analg 83(6): 1200-1205. The Safety and Efficacy of Oral Transmucosal Fentanyl Citrate for Pre Opin Anaesthesiol 18(6): 608-613. 49. Streisand JB, Stanley TH, Hague B, van Vreeswijk H, Ho GH, et al. Oral transmucosal fentanyl citrate premedication in children. Anesth Analg

69(1): 28-34. 54. Yuen VMY (2010) Dexmedetomidine: perioperative applications in children. Paediatr Anaesth 20(3): 256-264. 50. Schutzman SA, Burg J, Liebelt E, Strafford M, Schechter N, et al. (1994) Oral transmucosal fentanyl citrate for premedication of children 55. Roberts M, Stuart G (2013) Dexmedetomidine in Paediatric Anaesthe- undergoing laceration repair. Ann Emerg Med 24(6): 1059-1064. sia and Intensive Care. Anaesthesia Tutorial of the week 293. 51. Samarkandi A, Naguib M, Riad W, Thalaj A, Alotibi W, et al. (2005) 56. Hall JE, Uhrich TD, Barney JA, Arain SR, Ebert TJ, et al. (2000) Sedative, Melatonin vs midazolam premedication in children: a double blind, amnestic, and analgesic properties of small-dose dexmedetomidine placebo-controlled study. Eur J Anaesthesiol 22(3): 189-196. infusions. Anesth Analg 90: 699-705. 52. Kain ZN, MacLaren JE, Herrmann L, Mayes L, Rosenbaum A, et al. (2009) 57. Ebert TJ, Hall JE, Barney JA, Uhrich TD, Colinco MD, et al. (2000) The Preoperative melatonin and its effects on induction and emergence in effects of increasing plasma concentrations of dexmedetomidine in children undergoing anaesthesia and surgery Anesthesiology 111(1): humans. Anesthesiology 93(2): 382-394. 44-49. 58. The British National Formulary for Children (BNFc). 2013-2014. BMJ 53. Almenrader N, Haiberger R, Passariello M (2013) Steal induction in Group, The Royal Pharmaceutical Society of Great Britain, & RCPCH preschool children: is melatonin as good as clonidine? A prospective, Publications Ltd 2013. randomized study. Paediatr Anaesth 23(4): 328-333.